DESCRIPTION (Applicant's Abstract): The development of effective cocaine medications is needed as current psychological approaches and drug therapies have proven inadequate. Among candidate medications are dopamine transport inhibitors that, like cocaine, interact directly with the transporter and indirectly at dopamine receptors. In order to develop these candidate cocaine replacements, it is necessary to understand their effects on brain dopamine systems when chronically administered. The proposed experiments are designed to investigate the neurochemical consequences of chronic administration of potent dopamine transporter inhibitors on brain dopamine systems. Neurochemical assays will include assessment of dopamine transporter density and D1, and D3 dopamine receptors and receptor effector coupling. The latter will be analyzed using 35S-GTPgammaS in tissue and homogenates and by autoradiographic means. These studies will define which systems are regulated by chronic administration of candidate therapeutic drugs.